Impact of COVID-19 on Depression, Anxiety, Stress, Coping, and Grief in Pre-Health Professional Students in Lima, Peru.

Introduction: Peru had the world's highest death rate of COVID-19 with 213,000+ deaths and counting (Beaubien, 2021). Hospitalization and care for COVID-19 patients with limited resources has added stress to the shortage of frontline workers and resulted in students filling in the gap in acute care clinical settings. The purpose of this study was to examine the impact of COVID-19 on mental health (e.g., depression, anxiety, stress, and coping) and grief on undergraduate nursing and pharmacy students in Lima, Peru. Methods: This was a quantitative, descriptive study that examined students' self-report of mental health and grief at baseline during data collection. Results: Significant findings were reported in coping based on death of family member of COVID-19 (p = .02). Anxiety was positively correlated with grief (Rho = 0.35, p < .001), stress (Rho = 0.53, p < .001), and depression (Rho = 0.76, p < .001). Grief was positively correlated with stress (Rho = 0.25, p < .001) and depression (Rho = 0.39, p < .001). Finally, stress was positively correlated with depression (Rho = 0.51, p < .001). Discussion: This is the first study to explore nursing and pharmacy students' perceptions on how the COVID-19 pandemic impacted their mental health.

An electrophilic fragment screening for the development of small molecules targeting caspase-2.

Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been pentapeptides or peptidomimetics, face challenges for use as CNS drugs. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic fragment library from Enamine. Our two-point dose screen identified 64 Casp2 hits, which were further evaluated in a ten-point dose-response study to assess selectivity over Casp3. We discovered compounds with inhibition values in the single-digit micromolar and sub-micromolar range, as well as up to 32-fold selectivity for Casp2 over Casp3. Target engagement analysis confirmed the covalent-irreversible binding of the selected fragments to Cys320 at the active site of Casp2. Overall, our findings lay a strong foundation for the future development of small-molecule Casp2 inhibitors.

Did text-based news-media coverage about the COVID-19 pandemic increase vaccine uptake? A population-based study in Alaska.

COVID-19 vaccinations protect against severe infection, hospitalisation, and death. News media can be an important source of information for the public during a health crisis. This study explores the extent to which local or statewide text-based news coverage of the pandemic was related to the uptake of initial doses of COVID-19 vaccines among adults in Alaska. Multilevel modelling was employed to explore the association between news media intensity and vaccine uptake rates across boroughs and census areas, while controlling for relevant covariates. Results suggest that the intensity of news media did not significantly influence vaccine uptake during the majority of this time period and had a negative affect during the Delta-surge in the fall of 2021. However, the political lean and median age of boroughs or census areas were significantly associated with vaccine uptake. Race, poverty, or education were not significant determinants of vaccine uptake suggesting there are unique differences in Alaska compared to the U.S., particularly amongst Alaska Native people. The political environment in Alaska surrounding the pandemic was polarized. Future research in communications and channels that can cut through this polarized and politicized environment, and reach younger adults is needed.

Reference compounds for characterizing cellular injury in high-content cellular morphology assays.

Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.

Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.

Since the discovery of the caspase-2 (Casp2)-mediated ∆tau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and drug-likeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography. Regarding Casp2 selectivity, AcITV(Dab)D-CHO (23) and AcITV(Dap)D-CHO (26) demonstrated the best selectivity (1-6-fold), although these trends were only moderate. However, some analogous tetrapeptides, most notably AcDKVD-CHO (45), showed significantly increased Casp3 selectivities (>100-fold). Tetra- and tripeptides display decreased or no Casp2 affinity, supporting the assumption that a motif of five amino acids is required for efficient Casp2 inhibition. Overall, the results provide a reasonable basis for the development of both selective Casp2 and Casp3 inhibitors.

Coping Methods Used by College Undergraduate and Graduate Students while Experiencing Childhood Adversities and Traumas.

Experiences in childhood, both positive and negative, are crucial to a child's progression. Childhood traumas and adversities are detrimental to children's development and can have long term consequences that manifest themselves in young adulthood. The purpose of this study is to inductively explore coping strategies used by young adults during their experience of childhood traumas and adversities. A sample of college students from a diverse northeastern university (N = 146) provided quantitative and qualitative survey responses. Students were asked, "What were the tools you used to cope with adversity and/or traumatic events?" Participants responded to the prompt based on their experiences from childhood. The researchers analyzed the qualitative data using a mixed-method, thematic approach to coding participant responses. Additional quantitative information is explored to explain emerging qualitative themes. Two salient themes of coping strategies emerged, providing support for Machado et al. (2020): (1) Emotion-Focused Coping and (2) Problem-Focus Coping. Minor themes built on the findings in the area of Emotion-Focused Coping, highlighting processes of (i) emotional regulation, (ii) emotional expression, and (iii) emotional avoidance. Excerpts from this study's participants suggest that individuals dealing with adversities and traumas find a variety of ways to cope. These coping strategies can be implemented into institutions' everyday practices to aid children during their time of vulnerability. The article provides recommendations for school administrators, leadership teams, and any professional specializing in school culture, curriculum, and social work.

Securing Schools? Examining the Longitudinal Relationships Between Student Behavior and Engagement With Security Measures in Urban School Systems.

The use of school security measures has increased over the last two decades. Yet prior research suggests school security measures have a deterrent effect on student misbehavior. Existing studies often focus on school-level comparisons in security as opposed to examining how students within a given school differ in their interaction with security measures (i.e., within-school differences). To address this gap in the literature, the current study estimates the association between individual students' engagement with security and multiple forms of maladaptive student behavior in school. In particular, this study is guided by two research questions: 1) What is the relationship between students' engagement with school security measures and their engagement in problem behaviors; and, 2) To what extent do the relationships between engagement with security and student behavior problems differ by student race and ethnicity? Longitudinal data were collected from students at two separate time points in one academic year (N=359) across eight schools in one urban school district. Using a series of models to examine how students' engagement with school security measures is related to their perpetration of student behavior, findings highlight negative associations between engagement with school security and non-serious violent and weapons-related crime. While the school security change score and students' engagement in problem behaviors was no different for Black students than it was for students who were non-Black or non-Hispanic, the negative association between engagement with security and behavior indicated a stronger deterrent effect for Hispanic students. Findings suggest that engagement with school security should be examined at the within-school level and with consideration that racial and ethnic differences might vary from student to student within any given school. Moreover, long-term programming goals should be established when developing process for securing schools with emphasis on how security measures might influence individual students differently within the school setting.

Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314.

Alzheimer's disease (AD) was first described by Alois Alzheimer over 100 years ago, but there is still no overarching theory that can explain its cause in detail. There are also no effective therapies to treat either the cause or the associated symptoms of this devastating disease. A potential approach to better understand the pathogenesis of AD could be the development of selective caspase-2 (Casp2) probes, as we have shown that a Casp2-mediated cleavage product of tau (Δtau314) reversibly impairs cognitive and synaptic function in animal models of tauopathies. In this article, we map out the Casp2 binding site through the preparation and assay of a series of 35 pentapeptide inhibitors with the goal of gaining selectivity against caspase-3 (Casp3). We also employed computational docking methods to understand the key interactions in the binding pocket of Casp2 and the differences predicted for binding at Casp3. Moreover, we crystallographically characterized the binding of selected pentapeptides with Casp3. Furthermore, we engineered and expressed a series of recombinant tau mutants and investigated them in an in vitro cleavage assay. These studies resulted in simple peptidic inhibitors with nanomolar affinity, for example, AcVDV(Dab)D-CHO (24) with up to 27.7-fold selectivity against Casp3. Our findings provide a good basis for the future development of selective Casp2 probes and inhibitors that can serve as pharmacological tools in planned in vivo studies and as lead compounds for the design of bioavailable and more drug-like small molecules.

Social Determinants of Health and COVID-19 Behaviors and Beliefs Toward Immunizations Among Latinxs.

INTRODUCTION: Sixty million Latinxs make up 26.4% of all COVID-19 cases in the United States. It is uncertain whether behaviors and beliefs of immunizations among Latinxs is influenced by social determinants of health. The purpose of this study was to examine how social determinants of health predict COVID-19 behaviors and beliefs toward immunization among Latinxs. METHODS: In this exploratory study, 11 chapters from the National Association of Hispanic Nurses collaborated to recruit participants. The CDC National 2009 H1N1 Flu Survey was adapted to measure behaviors and beliefs about immunizations of COVID-19. The Health Access Survey was used to measure social determinants of health. Instruments were available in both Spanish and English. RESULTS: Participants (n=228) with higher education and health insurance tended to have less worry about taking the vaccine. Access to resources and practicing COVID-19 protective factors was positively associated. Alternative medicine and use of COVID-19 protective factors were negatively associated. Exposure to drugs and violence was associated with a decrease in likelihood to pursue a vaccine. CONCLUSIONS: Latinx need education about COVID-19 and vaccinations. Access to health care services must be available. Results highlight the importance of careful measurement when assessing social determinants of health among Latinx.

Synthesis of Guaianolide Analogues with a Tunable α-Methylene-γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity.

α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.

Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1ß and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.

Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α.

PURPOSE: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. EXPERIMENTAL DESIGN: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. RESULTS: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. CONCLUSIONS: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A.

A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 µM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 µM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.

3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.

A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 µM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 ± 0.0011 µM) and artemisinin (MRA1240, IC50 = 0.0086 ± 0.0010 µM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 µM) and Plasmodium vivax (IC50 = 0.0093-0.031 µM) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED50 value (50% effective dose) of 1.47 mg kg-1 day-1 following oral administration. The disubstituted triazine dimer 6k represents a new class of orally available antimalarial compounds of considerable interest for further development.

111In-DANBIRT In Vivo Molecular Imaging of Inflammatory Cells in Atherosclerosis.

Atherosclerosis-related morbidity and mortality remain a global concern. Atherosclerotic disease follows a slow and silent progression, and the transition from early-stage lesions to vulnerable plaques remains difficult to diagnose. Inflammation is a key component of the development of atherosclerotic plaque and consequent life-threatening complications. This study assessed 111In-DANBIRT as an in vivo, noninvasive SPECT/CT imaging probe targeting an inflammatory marker, Lymphocyte Function Associated Antigen-1 (LFA-1), in atherosclerotic plaques. Methods. Selective binding of 111In-DANBIRT was assessed using Sprague-Dawley rats exposed to filtered air and ozone (1 ppm) by inhalation for 4 hours to induce a circulating leukocytosis and neutrophilia in peripheral blood. After 24 hours, whole blood was collected and incubated with radiolabeled DANBIRT (68Ga-DANBIRT and 111In-DANBIRT). Isolated cell component smeared slides using cytospin technique were stained with Wright-Giemsa stain. Apolipoprotein E-deficient (apoE-/-) mice were fed either a normal diet or a high-fat diet (HFD) for 8 weeks. Longitudinal SPECT/CT imaging was performed 3 hours after administration at baseline, 4, and 8 weeks of HFD diet, followed by tissue harvesting for biodistribution, serum lipid analysis, and histology. 3D autoradiography was performed in both groups 24 hours after administration of 111In-DANBIRT. Results. Increased specific uptake of radiolabeled DANBIRT by neutrophils in the ozone-exposed group was evidenced by the acute immune response due to 4-hour ozone exposure. Molecular imaging performed at 3 hours using SPECT/CT imaging evidenced an exponential longitudinal increase in 111In-DANBIRT uptake in atherosclerosis lesions in HFD-fed mice compared to normal-diet-fed mice. Such results were consistent with increased immune response to vascular injury in cardiovascular and also immune tissues, correlated by 24 hours after administration of 3D autoradiography. Histologic analysis confirmed atherosclerotic disease progression with an increased vascular lesion area in HFD-fed mice compared to normal-diet-fed mice. Conclusion. 111In-DANBIRT is a promising molecular imaging probe to assess inflammation in evolving atheroma and atherosclerotic plaque.

ALARM NMR for HTS triage and chemical probe validation.

Nonspecific target engagement by test compounds and purported chemical probes is a significant source of assay interference and promiscuous bioactivity in high-throughput screening (HTS) and chemical biology. Most counter-screens for thiol-reactive compounds utilize mass spectrometry or fluorescence detection, and non-proteinaceous reporters like glutathione that may not always approximate the reactivity of protein side-chains. By contrast, a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) is an industry-developed protein-based [1H-13C]-heteronuclear multiple quantum coherence (HMQC) NMR counter-screen to identify nonspecific protein interactions by test compounds by reporting their tendencies to modulate the human La antigen conformation. This Current Protocol is a users-guide to the production of the 13C-labeled La antigen reporter protein, the reaction of test compounds with this reporter protein, as well as the collection and analysis of characteristic NMR spectra. Combined with other assay interference counter-screens, this assay will enhance chemical biology by helping researchers better prioritize chemical matter and which will increase the number of tractable HTS screening actives and aid in the development of better chemical probes.

GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity.

Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro-inflammatory response in vivo. In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions.

Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors.

Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.

Social Capital and Well-Being: Structural Analyses of Latina Mothers by Nativity.

Objective This study examined the direct and mediating effects of maternal social capital on health and well-being for native- and foreign-born Latina mothers and their children. Methods Data were drawn from the baseline and nine-year follow up waves of the Fragile Families and Child Well-being Study. The study included a sample of 874 Latina mothers. Mplus7 was used to perform structural equation modeling to determine whether exogenous indicators (age, education, and economic well-being) predicted social capital, whether social capital predicted mother and child well-being, and whether mediating effects helped explain each relationship. Results For native-born Latinas (n = 540), social capital did not predict maternal or child well-being. However, social capital significantly mediated the effects of age, education, and economic well-being on maternal well-being. For foreign-born Latinas (n = 334), social capital was a significant predictor of maternal well-being. Social capital also mediated the effects of age, education, and economic well-being on maternal, but not child well-being. Younger and foreign-born Latinas who report higher educational attainment and economic well-being have greater social capital, and thus better self-reported health. Conclusion Findings suggest that social capital is particularly relevant to the health of foreign-born Latinas. For all Latina mothers, social capital may serve as a protective mitigating factor to better health. Health service providers should evaluate the potential to integrate programs that promote social capital accumulation for Latinas. Further research should examine factors to improve the health of Latinas' children.